Axonal Degeneration Induced by Altered Redistribution of Ion Channels

Another mechanism of chronic demyelination-induced axonal degeneration may be triggered by the compensatory changes axons undergo to restore impulse conduction. Demyelination results in conduction block. An altered distribution of sodium channels along demyelinated axonal segments compensates for loss of myelin internodes permitting the resumption of action potential conduction and neurological function (Bostock and Sears, 1978; Foster et al., 1980; Felts et al., 1997). Change in channel distribution, however, can also make these axons more susceptible to degeneration by increasing energy demand when energy production may be compromised (see Chapter 7). The greatest consumption of ATP in the CNS is by Na/K ATPases for the maintenance of ionic gradients necessary for neurotransmission (Ames, III, 2000). When axons are demyelinated energy consumption is greatly increased as a result of the redistribution of Na channels and the resulting increased influx of sodium. As mentioned earlier, ATP production may be compromised by oxidative damage to the mitochondrial enzyme complexes. In addition, slowing of axonal transport resulting from demyelination and decreased ATP availability may decrease rates of mitochondrial renewal. Collectively, all these factors will eventually result in the axon operating with an energy deficit leading to ionic imbalances (Stys et al., 1992; Leppanen and Stys, 1997). Several recent reports in EAE indicate axonal degeneration is Ca-mediated (Craner et al., 2003, 2004). Excess axonal Ca may result from reversal of Na/Ca exchangers caused by increased axonal Na levels as a result of insufficient ATP to run the Na/K ATPases (Stys et al., 1992; Agrawal and Fehlings, 1996; Li et al., 2000).

Collectively, the aforementioned studies indicate that myelin-forming glia exert trophic effects on axons at a local

Figure 7 Axonal loss and spinal cord atrophy in paralyzed MS patients. Reduced neurofilament staining indicates significantly decreased axonal density in a demyelinated area of the gracile fascicle from MS cervical spinal cord (B) compared to matching control sample (A). Measures of axonal loss in spinal cords from 5 chronic MS patients at cervical (C5), thoracic (T5), and lumbar (L5) levels averaged 68% (C). Whole spinal cord cross sections (mm2) from controls and chronic MS patients with severe neurological impairment were measured at cervical (C5-C7) and lumbar (L1-L3) levels to determine the percent change in area between MS and control (C). Average MS spinal cord area was reduced, significantly at the cervical level (P = 0.02). (Reproduced from Bjartmar et al., 1999 (A, B) and Bjartmar et al., 2001 (C) with permission.)

Figure 7 Axonal loss and spinal cord atrophy in paralyzed MS patients. Reduced neurofilament staining indicates significantly decreased axonal density in a demyelinated area of the gracile fascicle from MS cervical spinal cord (B) compared to matching control sample (A). Measures of axonal loss in spinal cords from 5 chronic MS patients at cervical (C5), thoracic (T5), and lumbar (L5) levels averaged 68% (C). Whole spinal cord cross sections (mm2) from controls and chronic MS patients with severe neurological impairment were measured at cervical (C5-C7) and lumbar (L1-L3) levels to determine the percent change in area between MS and control (C). Average MS spinal cord area was reduced, significantly at the cervical level (P = 0.02). (Reproduced from Bjartmar et al., 1999 (A, B) and Bjartmar et al., 2001 (C) with permission.)

level, and that disruption of the axonal cytoskeleton plays a critical role in mediating the pathogenesis of axonal degeneration secondary to demyelination. Consequently, the effects of chronic demyelination may drive late axonal degeneration in SP-MS by inducing deleterious compensatory changes by the axolemma and altering axonal transport. Further, chronic demyelination results in unresolved loss of trophic support from myelin-forming cells. Therefore, remyelination is important not just for restoring normal impulse conduction, but as a neuroprotective event for ameliorating mechanisms of late axonal degeneration.

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